Administration of physiologically active agents through the skin (‘transdermal delivery’) has received increased attention because it not only provides a relatively simple dosage regime but it also provides a relatively slow and controlled route for release of a physiologically active agent into the systemic circulation. However, transdermal drug delivery is complicated by the fact that the skin behaves as a natural barrier and therefore transport of agents through the skin is a complex mechanism.
Structurally, the skin consists of two principle parts, a relatively thin outermost layer (the ‘epidermis’) and a thicker inner region (the ‘dermis’). The outermost layer of the epidermis (the ‘stratum corneum’) consists of flattened dead cells which are filled with keratin. The region between the flattened dead cells of the stratum corneum is filled with lipids which form lamellar phases that are responsible for the natural barrier properties of the skin.
For effective transdermal delivery of a physiologically active agent that is applied to the surface of the skin (‘topical application’), the agent must partition firstly from the vehicle into the stratum corneum, it must typically then diffuse within the stratum corneum before partitioning from the stratum corneum to the viable epidermis.
To overcome some of the problems with transdermal delivery that are associated with transport across the dermal layers (‘percutaneous absorption’), physiologically active agents are commonly formulated with dermal penetration enhancers (Finnin and Morgan, J. Pharm. Sci., Vol 88, No. 10, October 1999, pp 955-958) which are often lipophilic chemicals that readily partition into the stratum corneum whereupon they exert their effects on improving the transport of drugs across the skin barrier.
A transdermal “patch” typically consists of a matrix or reservoir containing the drug to be administered, together with a backing layer, an adhesive and a protective release liner. Release membranes may also be incorporated. The delivery of drugs through these systems is either through passive diffusion, controlled by a semi-permeable release membrane, or is controlled by the adhesive/adhesive matrix. The system may also incorporate drug penetration enhancers to increase the flux of the drug through the skin.
One of the drawbacks of the current approaches is that the formulations are typically in continuous contact with the skin. Creams and ointments or adhesives used in patches can cause skin irritation and sensitisation. A significant proportion of patch users suffer from skin irritation and sensitisation due to adhesives used in the patch.
The rate of drug delivery across a dermal surface can be increased by dermal penetration enhancers. The problem with most known dermal penetration enhancers is that they are often toxic, irritating or allergenic. These enhancers tend to be proton accepting solvents such as dimethylsulfoxide and dimethyacetamide. More recently, 2-pyrrolidine, N,N diethyl-m-toluamide (Deet), 1-dodecal-azacycloheptane-2-one (Azone), N,N dimethylformamide, N-methyl-2-pyrrolidine and calcium thioglycolate have been reported as effective enhancers. However, difficulties remain with such dermal enhancers because the problem of irritation at the site of application has not been overcome.
The most critical problem with these compounds however is their toxicity. If a compound when used as a dermal enhancer is toxic, irritating or allergenic, then that compound is unsuitable for application to the animal body. Dimethyl acetamide is not clinically acceptable for these reasons. Although Deet and Azones have lower reported toxicities, their toxicity is still such that they are not widely used. It is possible that Azone and dimethyl sulfoxide may be employed as a dermal penetration enhancer if the amount applied is sufficiently small so as not to be appreciably toxic, irritating or allergenic to the animal.
The compositions of the present invention are suitable for use as vehicles for the topical application of specific compounds to the skin using pharmaceutical, nutraceutical, cosmetic or veterinary preparations. Such topical application enables the specific compounds to penetrate the skin and enter the circulatory system thereby enabling the active compound (s) to have a systemic effect. The at least one active compound may be a pharmacologically active compound. A “pharmacologically active compound” is a compound that has a therapeutic effect on the human or animal body in the treatment or prevention of a condition.
The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.